Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 53, Issue 19, Pages 7236-7250Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm100959g
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- University of Berne
- Swiss National Science Foundation
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A variety of conformationally constrained aspartate and glutamate analogues inhibit the glutamate transporter 1 (GLT-1, also known as EAAT2). To expand the search for such analogues, a virtual library of aliphatic aspartate and glutamate analogues was generated starting from the chemical universe database GDB-11 which contains 26.4 million possible molecules up to 11 atoms of C. N. O, F, resulting in 101026 aspartate analogues and 151285 glutamate analogues. Virtual screening was realized by high-throughput docking to the glutamate binding site of the glutamate transporter homologue from Pyrococcus horikoshii (PDB code: 1XFH) using Autodock. Norbornane-type aspartate analogues were selected from the top-scoring virtual hits and synthesized. Testing and optimization led to the identification of (1R*,2R*,3S*,4R*,6R*)-2-amino-6-phenethyl-bicyclo[2.2.1]heptane-2,3-dicarboxylic acid as a new inhibitor of GLT-1 with IC(50) = 1.4 mu M against GLT-1 and no inhibition of the related transporter EAAC1. The systematic diversification of ligands by enumeration with help of GDB followed by virtual screening, synthesis. and testing as exemplified here provides a general strategy For drug discovery.
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